FDA Participants

Bram Zuckerman

Director

Division of Cardiovascular Devices

John P. Holden, Ph.D.

Lead Reviewer

Wolf Sapirstein, M.D.

Clinical Review

Barbara Krasnicka, Ph.D.

Statistical Review

CALL TO ORDER

Acting Panel
Chair Warren Laskey, M.D., called the meeting to order at 9:01 a.m. and stated
that the purpose of the meeting was to discuss and make recommendations on PMA
P910001/S022 for the Spectranetics CVX-300® Excimer Laser System to
treat critical limb ischemia (CLI). Executive Secretary Geretta Wood
read the conflict of interest statement. Mitchell Krucoff, M.D., and
Christopher J. White, M.D., were given full waivers for their interests in
firms for matters that could be affected by the panel’s recommendations. She
added that FDA took into consideration other matters regarding Dr. Krucoff’s
and Cynthia M. Tracey’s, M.D., past or current interest involving firms at
issue but in matters not related to the day’s agenda. She also noted that
Industry Representative Michael Morton has reported interest in firms at issue.
Dr. Laskey then asked the panel members to introduce themselves.

Chris Reiser,
Ph.D., vice president for Technology and Clinical Research at Spectranetics,
introduced the sponsor presenters and gave a brief background of the
development of the excimer laser. The CVX-300® uses a XeCl laser
that emits a pulse of ultraviolet light at 308 nanometers through fiber optic
catheters, and was first approved in 1993 by the FDA for use in coronary
arteries. Dr. Reiser noted that this system is currently being used in the
United States for coronary atherectomies and pacing lead removal, and in Europe
for peripheral atherectomies. The fibers deliver the UV light directly to the
tissue, directly penetrating about 50 microns into the tissue.

Dr.
Reiser said that they became interested in using the system for peripheral
arterial disease (PAD) when they noticed that PAD shared some of the same
indications as cardiac disease. In February 1999, FDA approved the Laser
Angioplasty for Critical Limb Ischemia (LACI) Phase 1 Registry. LACI Phase 1
was a 25-limb study using excimer laser atherectomy to open blocked arteries
near or below the knee in patients presenting non-healing ulcers or gangrene.
This study resulted in limb salvage for 70 percent of patients who were poor
surgical candidates. Based on this and other data, FDA approved a pivotal
trial, LACI Phase 2, in January 2001.

John
Laird, M.D., Washington Hospital Center, presented the protocol and results
of the LACI Phase 2 Registry. He said that the patients in this study had CLI
with advanced PAD, and classified in the literature as Fontaine III or IV, or
Rutherford 4, 5, or 6. Only a minority of patients presented with lesions
suitable for balloon angioplasty. Dr. Laird referred to the patients chosen for
the study as “no option” patients.

Dr.
Laird discussed why the LACI 2 study was not randomized. The investigators
decided to include patients in the trial that were poor surgical candidates,
which removed surgical by-pass from the randomization scheme. Percutaneous
transluminal angioplasty (PTA, or balloon angioplasty, was rejected as an
appropriate randomization strategy for these patients because the results of
previous trails in the literature were variable, retrospective single-center
studies; in addition, there have been no randomized trials comparing PTA with
other therapies in the past 15 years. He added that the TransAltantic
Inter-Society Consensus (TASC) Working Group document recommends PTA for CLI
only in simple lesions. In fact, Dr. Laird noted, about 88 percent of patients
in the LACI 2 trial had TASC lesion types C and D, with complex patterns and
long diffuse disease. He added that that no study in the literature has made
balloon angioplasty the “gold standard” in treating CLI.

Given
these limitations, Dr. Laird said that the investigators decided that their
best option was to use historical controls for the LACI 2 study. They decided
to use an Italian multi-center randomized study of prostaglandin E1 in CLI
patients, published in Annals of Internal Medicine in 1999, by the
Ischemia Cronca Critica degli Arti Inferiori Study Group, or ICAI. The study
conformed to the TASC definitions and good clinical practices, he noted. Dr.
Laird discussed the details of the Italian study, stressing that ICAI
statistics set a high benchmark for the standard of care in CLI patients, with
lower or expected levels of mortality compared to the published literature for
CLI, and a low frequency of major amputation.

Dr.
Laird next presented the LACI 2 study design. He noted that LACI 2 is the first
study of its kind, being a prospective, multi-center study evaluating a device
for the treatment of CLI. LACI 2 patients had CLI with a Rutherford category of
4 through 6, and were felt to be poor surgical candidates because they had at
least one of the following conditions: poor or absent vessel for outflow
anastamosis; absence of a venous conduit; American Society of Anesthesiology
(ASA) classification of 4 or higher for high risk of surgical morbidity. The
treatment consisted of ELA of the superficial femoral artery (SFA), popliteal
and/or infrapopliteal arteries with adjunctive balloon angioplasty and optional
stenting. The study used laser catheters no larger than 2.5 mm in diameter. The
primary effectiveness endpoint of the trial was limb salvage (freedom from
amputation at or above the ankle) at 6 months, and the primary safety endpoint
was death within 6 months following the procedure.

A total of 145
patients with 155 legs were enrolled in the study between April 2001 and April
2002 at 14 sites, including three German sites. In general, according to Dr.
Laird, there were significant differences in patient morbidities between the
LACI trial and the control group; for example, nearly half of the patients in
the LACI group were women, compared to 28 percent in the control group, and 66
percent of the LACI patients suffered from diabetes mellitus versus 39 percent
in the control group.

Dr.
Laird presented two case profiles of patients enrolled in the LACI 2 study, and
also viewed several sets of patient photographs that documented baseline
conditions and follow-up at three and 6 months, using digital morphography to
measure the area of the ulcers. Dr. Laird noted that they have collected a
large library of such photographs.

Dr.
Laird provided the panel with results from the LACI 2 trial, including
information about lesion types, LACI procedure results, and angiographic
results. Stent implantation was performed in 45 percent of cases and adjunctive
PTA was performed in 96 percent of cases. Procedure success, defined as less
than 50 percent residual stenosis in all of the lesions treated in a given limb
was 85 percent. Straight line flow to the foot was established in 89 percent of
the cases. Half of the improvement in luminal gain following intervention was a
result of ELA. The median hospital stay was 1 day; mean was 3 days.He also presented representative angiograms
from the study.

Dr.
Laird discussed the treatments performed in the ICAI control study, noting that
43 percent of patients underwent some kind of surgery or angioplasty, while 57
percent underwent more conservative supportive care with such treatments as
analgesics, oxygen therapy, etc.

Comparing the
two study groups for serious adverse events, Dr. Laird asserted there was no
difference in terms of mortality or major amputation, and nonfatal myocardial
infarction (MI) or stroke. However, he noted a higher re-intervention rate in
the LACI 2 group, 17 percent versus 4 percent. He explained this by noting that
the 4 percent reflects the entire control study, and that among the 43 percent
of control patients who underwent some surgical or angioplasty treatment, the
re-intervention rate is 11 percent. He said that this makes the 17 percent in
the LACI 2 group compare favorably with the control and any other study. Dr.
Laird added that the incidence of LACI patients with acute limb ischemia or the
need for bypass surgery or endarterectomy was low during the follow-up time
period.

Dr. Laird went
over the study’s 6-month results. The data can be analyzed several ways, he
said. Looking at the data on a per patient basis, the study enrolled 145
patients; 15 patients died during the follow-up period, with 2 dying after
having gone through major amputation. Eleven patients were lost to follow-up,
leaving 119 patients who reached their 6-month endpoint. Major amputation was
required in 9 of the 119, so 110 patients survived with limb salvage.
Approaching the data using an “intent-to-treat analysis,” considering all
deaths and the loss-to-follow-up patients as treatment failure, the limb
salvage rate is 76 percent (110 patients with limb salvage out of the original
145 patients). Dr. Laird, asserted, however, that the more accurate way to
analyze the data is to consider the numbers who survived: 110 patients (92
percent) survived with limb salvage out of the 119 patients who reached their
6-month endpoint. The results are similar when looking at the data on a per
limb basis.

According to Dr.
Laird, there was no difference between the LACI group and the control group
when comparing the main endpoints at 6 months, so he feels that the study did
not negatively alter the natural history of the LACI patients. He presented an
analysis of the ulcer healing success and functional outcomes. He also looked
at the impact of stenting in the study, noting that there was no statistical
difference in the limb salvage rate between those limbs that were stented and
those that were not.

Dr. Laird ended
his presentation by noting that the outcomes met all of the hypotheses in the
study protocol, and the statistics met the benchmarks of safety and
effectiveness. He also covered the clinical benefits of the LACI treatment,
including limb salvage without affecting patients’ chances of survival or
significantly increasing their risk of serious adverse events.

Panel Questions for the Sponsor

Dr.
Krucoff asked Dr. Laird about the learning curve in applying this technology to
CLI. Dr. Laird said that he had no data but that he sensed that the learning
curve was relatively short. Dr. Somberg asked what would happen to these
patients, given that they were not good surgical candidates, if they had not
received ELA. Dr. Laird thought that a significant percentage might have been
treated with amputation, while some would have been referred to surgery and
received a distal bypass with synthetic grafts, and others may have undergone
PTA or other modalities.

Dr. Laskey
suggested that some of the statistics had been glossed over in the sponsor’s
presentation, and asked why a delta of 10 was chosen. Dr. Reiser responded that
[his response is not on
the microphone so it’s unintelligible]. Dr. Normand asked what the delta
would have been if the two populations had been randomized, but Dr. Reiser said
that this issue never came up. Other questions about the study included those
regarding perforation of vessels, the definition of “inadequate venous
conduit,” the number of ASA class 4 patients, and problems resulting from the
lack of raw data from the Italian study.

FDA PRESENTATION

John
P. Holden, Ph.D., Division of Cardiovascular Devices, FDA lead reviewer,
presented the FDA Review Team for this PMA and provided a history of the clinical
trial and the PMA application. He read the proposed indications for using the
CVX-300® Excimer Laser System in treating CLI, as well as the device
description. He noted that the device description also includes 15 models of
the Spectranetics ELA catheters. The three types of catheters evaluated in the
LACI trial included over-the wire (Extreme and Extreme II), rapid exchange
(Vitesse), and eccentric (Vitesse E). He noted that the peripheral catheters
underwent preclinical testing, and that there were not additional questions
about this from FDA. Dr. Holden included in his history of the trial portions
of the FDA conditional approval letter for the pivotal trial covering
risk-benefit analysis and the necessity of showing that stenting did not
confound the analysis of the study endpoints.

Wolf
Sapirstein, M.D., Division of Cardiovascular Devices, provided the FDA’s
clinical summary. Dr. Sapirstein went over the LACI 2 study’s design and a
description of the patient population. He said that, because of the study’s
single-arm design and historical control, the outcomes from this study were
open to conflicting interpretations. However, he added that the study was
well-conducted and monitored. Dr. Sapirstein discussed the problems faced by
the sponsor because of their choice to use an historical control, including
lack of access to the original ICAI data, which made it difficult to compare
many important secondary endpoints for the treatment of CLI in the two studies.
He noted that the sponsor justified the nonrandomized design because there were
no suitable alternative treatments for these patients. Dr. Sapirstein, however,
asserted that a literature review shows that these patients can be managed with
a variety of alternative treatments.

Dr.
Sapirstein discussed the standards used to include patients in the LACI 2
study, and determined that significant differences exist between the study’s
planned criteria and its actual criteria. For example, only 46 percent were
classed at ASA 4 or above, and only 32 percent did not have a suitable
autogenous vein. Moreover, he noted that the sponsor’s claim that the LACI
patients were more comorbid and at a greater risk for poor outcomes than the
ICAI patients can be disputed. In examining the LACI procedure, Dr. Sapirstein
concluded that, because PTA was used in all of the LACI cases, the angioplasty
alone might have been effective without ELA. Use of stents in 45 percent of the
cases obscures the issue of successful treatment with ELA, as well, he said. He
also noted that the incidence of required re-intervention was significantly
higher in the LACI group versus the ICAI group, and persisting CLI was about 30
percent in both groups.

In
the final analysis, Dr. Sapirstein said that while LACI did achieve equivalent
patient survival with limb salvage as compared with the ICAI group, any benefit
from this treatment was diminished by the high incidence of re-intervention and
by CLI persistence. As well, the value of balloon angioplasty in the management
of CLI remains unclear.

Barbara
Krasnicka, Ph.D., Division of Biostatistics, said that her presentation
would focus primarily on the problems with the LACI study’s design and
statistical analysis. She discussed the statistical analysis issues related to
the study’s primary effectiveness endpoint and for one of the secondary
endpoints, survival time in 6 months of the follow-up. She expressed concern
that there was no data at the individual patient level for the control group,
only summary statistics.

Dr.
Krasnicka discussed the sponsor’s objective of showing that the results in the
LACI group would be at least as successful as those in the control group. The
FDA agreed to the study’s equivalence design assuming that the LACI patients
were sicker than the control patients. The primary effectiveness endpoint was
met in 75.9 percent of the LACI patients and in 73.4 percent of the control
group patients, with a 95 percent confidence interval (-5.3 percent, 10.2
percent). Dr. Krasnicka said that these results show no statistical difference
between the two groups.

Limitations to
an analysis of the primary endpoint included the fact that the study was not
randomized, making the treatment results uncertain, she said. The results may
have been affected by the fact that the LACI patients and the control group
patients were not comparable, and the two studies took place in different
hospitals and countries. Additional factors affecting the results included the
unavailability of raw data from the control group, missing data, and differing treatment
modalities in the two groups.

Dr. Krasnicka
examined one of the secondary endpoints, the survival time in 6 months, using
Kaplan-Meier estimates. The visual impression of the Kaplan-Meier estimates
suggested that the LACI patients could survive longer than the control
patients. However, according to the Wilcoxon test, the difference between the
two groups is not significant at the .05 level, where the P value is .1728. Dr.
Krasnicka also looked at the limitations to an analysis of the secondary endpoint.
These limitations included the heterogeneity of the LACI patients, which could
affect treatment comparisons; non-stratified comparison of survival times; the
interactions of covariates that could have influenced treatment effects; the
differences between the LACI and control groups; and the use of ELA with
adjunctive PTA. These limitations contributed to questionable survival
analyses, she said.

Dr. Sapirstein
concluded the FDA’s presentation by providing the panel with a summary of their
review.

Panel Questions for FDA

The questions
for the FDA focused on the study’s use of an equivalency hypothesis and the
choice of a control group that differed with the LACI group in significant
ways. A number of panel members expressed doubt as to whether equivalency
proved treatment effectiveness in this trial.

Dr. Sapirstein
noted that an equivalency hypothesis was accepted for effectiveness but not
safety reasons, because the patients in the LACI group were facing inevitable
limb loss. He said that the FDA believed the control group statistics to be
sufficiently robust. Dr. Zuckerman noted that FDA gave only conditional
approval to the study design, and not a total endorsement of the trial.

Several panel
members expressed concern about FDA guidance in this trial, the sponsor’s
reading of the literature, what the laser treatment added to other
interventions and therapies, and whether the results of the ELA treatment could
truly be understood given the study’s design.

OPEN COMMITTEE DISCUSSION

After
providing a brief summary of the study protocol, Panel MemberGary G.
Nicholas, M.D., presented his concerns about the LACI protocol. A stronger
control group, he noted, would have received only balloon angioplasty and
stenting without ELA. The lack of such a control group, Dr. Nicholas said, made
it difficult to see the actual benefits of ELA. As well, the assumption that
the LACI patients were less sick than the ICAI patients does not contribute
toward the sponsor’s argument of equivalency.

Dr. Nicholas
continued his discussion of concerns by noting that the rates of patients
reaching the primary safety endpoint in the two groups were not significantly
different, and cast doubt on the medical fitness difference in the two groups.
The multiple comparisons of the LACI group to the surgical and medical
literature failed to achieve Level 1 or Level 2 evidence. For example, the
control group contained a significantly larger number of men and current
smokers than did the LACI group. In addition, the control group did not use the
Rutherford classification for chronic lower limb ischemia. As well, the LACI
study’s inclusion of patients classified as Rutherford category 6 was
questionable, as the stated protocol was limb salvage. Dr. Nicholas noted that
the sponsors indicated that they measured ankle indices upon patients’ entry
into the study and at regular intervals, but these data are not included in the
proposal.

The
effectiveness of the procedure is unclear, he said, because 6 months after the
procedure 39 percent of the LACI patients remained in Rutherford class 4, 5, or
6; 43 percent in the control population also had continuing CLI. The
information for the occurrence of adverse effects stops at 6 months, but Dr.
Nicholas said he would be interested in knowing what happened to these patients
after that period.

Dr. Nicholas
asserted that the “gold standard” for care of CLI is distal bypass grafting
with a venous conduit, and he expressed concern that the investigators did not
evaluate their patients for alternate sites for venous conduits. He added that
ASA classification 4, used by the study to include patients, is common among
the patients of vascular surgeons.

LACI
Investigator Venkatesh Ramaiah, M.D., Arizona Heart Hospital, responded to
questions from the panel about the possibility of graftable vessels and the
prominence of renal therapy in LACI patients. He stressed that the primary
purpose of the study was to evaluate patients not appropriate for surgery.

Bruce Gray,
D.O., Greenville Memorial Hospital and LACI investigator, addressed a panel
question about the avoidance and use of stents in the study’s patients. He
noted that using a laser through an occlusion removes the chronic thrombus
there, changing the conditions such that using a stent and a balloon becomes safer.
Also, the number and length of stents are decreased with this method.

Dr. Reiser
responded to a panel question about how the ICAI study was selected as the
control study. He said that they did an extensive search in the balloon
angioplasty literature and in other modalities to find the standard of care for
this particular patient group. Between LACI 1 and LACI 2 the ICIA study paper
appeared, fulfilling the sponsor’s desire to set a high benchmark and find a
standard of care against which the LACI study could compete.

Dr. Reiser also
responded to Panel Member William Maisel’s, M.D., question about the 128
patients who were screened out of the study, noting that no follow-up was done
on these patients. Dr. Maisel suggested that this data would have been helpful.
Dr. Laird also responded to Dr. Maisel’s questions about the pace of
re-intervention and whether 6 months was too short for a follow-up period, by
noting that pace of serious adverse effects did not seem to increase as time
progressed.

Christopher White, M.D., panel member,
added his voice to the other panel members who commended the investigators for
the execution of the trial, despite the disappointing design of the trial. He
asked the sponsors about the average fluence per lesion, and Dr. Reiser said
that the mean maximum fluence was 51 mJ/mm2, mean repetition rate
was 32 pulse per second, and mean laser pulses per limb were 5,371. Dr. White
said he was concerned that angioplasty was not chosen as the design for this
trial because he believes that the laser is actually an adjunctive treatment.
He added that the data do not allow him to determine what the laser adds to the
treatment of CLI. As well, he said that he does not believe that the treatment
in the ICAI study is the standard of care for CLI patients.

Panel members
brought up the issue that there are numerous studies in the literature that
show good results with PTA, despite the sponsor’s argument that many of the
studies showed poor results. Dr. Laird discussed some of the literature, but
stated that the study showed excellent results, especially considering the
difficult patient population, by using a strategy of laser first followed by
other modalities. He noted that investigators did not want to randomize against
a treatment they did not believe would work for these patients, such as PTA.

John C.
Somberg, M.D., panel member, brought up the issue of the various techniques
involved in using the ELA, and what could be learned from the fact that in
about 13 percent of the LACI patients, investigators were not able to cross the
lesion with a guide wire. Dr. Ramaiah noted that an important feature of the
device was that being able to initiate the procedure with the laser still
helped these patients. Dr. Somberg suggested that this possibly indicated a
subset of patients to whom the laser should be made available, but that the
weaknesses in the study’s design precluded a complete understanding of this.

Dr. Krucoff,
panel member, acknowledged that the investigators and sponsors were
“passionate” about the work they undertook. He referred back to the FDA
conditional approval letter and discussed with Dr. Reiser the possibility of
the confounding effect of stents on the study’s results and whether the
sponsors looked at any quality of life measurements. Dr. Reiser said that the
study did provide ISO standard risk analysis, but that was different than the
traditional qualitative risk/benefit analysis. Dr. Krucoff said he believed
that this patient population could be randomized against standard care, opening
the door to other ways to gather information on risks and benefits that are not
death or amputation.

Panel member
Sharon-Lise Normand, Ph.D., asked about the appropriateness, from a
statistical standpoint, of having less than 50 percent of the LACI patients ASA
class 4, or high surgical risk. Dr. Reiser said that this was a marker of
expected mortality under surgical conditions. She noted that if she looked at
the variables one at a time the LACI group appeared sicker and at other times
the ICAI group seemed sicker. This made it impossible, according to Dr.
Normand, to analyze the statistics and find the delta for these two groups,
because they are not comparable. She also addressed the study’s safety
endpoint. The sponsor’s contention that the LACI group is sicker prompts
concern, she noted, about the lack of information related to this group’s
larger number of patients lost to follow-up. Dr. Normand also questioned
whether the variables used to characterize the two cohorts, as well as the
endpoint, are measured the same way for the two groups.

OPEN PUBLIC SESSION

No
comments were made.

PANEL QUESTIONS

1(a)Please
comment
on whether or not the characteristics of patients in the LACI trial and the
control group demonstrate an increased risk for limb loss in LACI, sufficient
to justify the 10 percent difference for the primary effectiveness endpoint.

The panel concurred that there is
not enough evidence to justify the 10 percent difference for the primary
effectiveness endpoint and the entire concept of the study design because of
the inability to compare the two groups.

1(b) An active intervention
for limb salvage in LACI is compared to a control arm of non-intervention.
Please comment on whether the outcomes for this endovascular procedure can be satisfactorily
assessed without comparisons to balloon percutaneous transluminal angioplasty
(PTA).

The panel concurred that the
outcomes cannot be assessed or compared without more in-depth knowledge of the
LACI patient population and the Italian study.

2.Re-interventions were significantly higher in the LACI study than
the control group. Please comment on whether the adverse event data from the
LACI study provide reasonable assurance of the safety of ELA used to treat CLI.

The panel concurred that the adverse
event data from the LACI study provide reasonable assurance of the ELA safety
to treat CLI, when compared to the literature. Two panel members expressed
concern, however, about the upward trend of adverse effects, and whether that
continued after the 6-month follow-up period.

3.The clinical objectives of the study were stated as: (i)
protection from acute amputation; (ii) limb salvage; (iii) resolution of CLI;
and (iv) preservation of surgical options. Please comment on whether the
outcomes for the LACI study demonstrate that these objectives have been
achieved.

The panel concurred that the study
provided a measure of safety but no convincing measure of efficacy.

4.Please comment on the added value provided by the laser therapy,
which is used as an adjunct prior to the PTA required for final resolution of
the lesion obstruction.

The panel concurred that the study
did not present enough data to understand clearly the added value provided by
the laser therapy.

5.Please comment on whether the benefit demonstrated in this study,
particularly with respect to quality of life-years, outweighs the adverse
events that occurred and the persistence of CLI documented.

The panel members commented that
the sponsor did not provide enough information to make a judgment on whether
the benefit of the treatment outweighs the adverse events.

6.Labeling for a new device should indicate which patients are
appropriate for treatment, identify potential device-related adverse events,
and explain how the device should be used to optimize its risk/benefit profile.
If you recommend device approval, please address the following:

(a) Do the Indications for Use, as stated below,
adequately define the patient population and procedural use for which the
device will be marketed?

The Spectranetics CVX-300® Excimer Laser System
is indicated for facilitation of limb salvage in patients with critical limb
ischemia (associated with Rutherford Categories 4, 5, and 6) who have
angiographically evident culprit stenosis and/or occlusions in the SFA,
popliteal and/or infrapopliteal arteries, who are poor surgical candidates, and
who are acceptable candidates for revascularization.

The panel concurred that they could
not address this question based on the continuing questions about the device’s
efficacy.

(b) Based on the study results, please discuss
whether the proposed warnings, precautions, and contraindications are
acceptable.

The panel concurred that the
Indications for Use are well-written, given the questions about the device’s
efficacy.

(c) Please discuss whether the instructions for use adequately
describe how the device should be used.

The panel concurred that the
instructions for use should be clearer on nonprotocol approaches and technical
nuances in the area of stents and guide wires.

7.Please indicate if the following findings are sufficiently robust
to warrant incorporation in the label:

(b) Seventy limbs in the LACI study also required
stent placement. Stents were placed in 56 superficial femoral arteries (SFAs)
in the 104 limbs with SFA lesions. Forty-nine (87.5 percent) of the SFAs with
stents remained amputation-free at six months.

The panel concurred that both
statements should stand as written.

8.The sponsor has proposed the following training requirements in
the draft Instructions for Use:

The use of the CVX-300® Excimer Laser System is
restricted to physicians who are trained in atherectomy, Percutaneous
Transluminal Coronary Angioplasty (PTCA) and who meet the training requirements
listed below. These requirements include, but are not limited to:

1. Training of laser safety and physics.

2. Review of patient films of lesions that meet the
indications for use.

3. A review of cases demonstrating the CLiRpath catheters in
lesions that meet the indications for use.

4. A review of laser operation followed by a demonstration of
the CVX-300® Excimer Laser System.

5. Hands-on training with the CVX-300® Excimer
Laser System and appropriate model.

6. A fully-trained Spectranetics representative will be
present to assist for a minimum of the first three cases.

7. Following the formal training session, Spectranetics will
make available additional training if so requested by the physician, support
personnel, the institution or Spectranetics.

Please comment on whether these training requirements are adequate.

Panel members requested that the
use be restricted to physicians trained in peripheral vascular intervention,
not PTCA; that the qualifications for use include a physician credentialed in
angioplasty. Panel members discussed who would be best to assist with
training—a proctor, a company representative, or other. Dr. Laskey suggested
that a patient information brochure be added to the materials.

Additional Comments

Dr. Laskey asked
if the FDA has any additional comments. Dr. Zuckerman said they did not have
any additional comments. He asked the sponsors if they had any additional
comments. Dr. Laird acknowledged that there were limitations to the study’s
design. He also noted the challenges in trying to demonstrate efficacy against
an historical control in which a majority of the patients did not receive an
intervention. However, he said that he was confident that the sponsors had
demonstrated safety and excellent results in this device in a population of
very sick people.

Dr. Laskey
solicited comments from the panel’s industry representative. Mr. Morton
recognized the work that went into the day’s presentations and thanked FDA for
clarifying the requirements for valid, scientific evidence.

Dr. Laskey then
asked the panel’s consumer representative, Allen Hughes, Ph.D., of George
Mason University, for any comments. Dr. Hughes also commended the meeting
participants for their presentations. He asked if the sponsors knew whether any
of the LACI patients who had a limb amputated were good candidates for
prosthetic devices. Dr. Ramaiah said that studies have shown that patients who
undergo revascularization experience a much higher quality of life when
compared with patients who must undergo amputation. Dr. Hughes also asked about
alternative treatments and whether the ELA treatment is considered the last
option before amputation. Dr. Laird responded that this was generally the case.

VOTE

Ms. Wood read
the voting options. Dr. Nicholas moved to deny approval of the PMA; the motion
was seconded. The panel voted 9 to 1 in favor of denying approval of the PMA.
Dr. Laskey asked each panel member to state their vote and the reasons for
their vote.

Several
panel members stated that they felt that while there was a need for such a
product, the sponsors must design a study with an appropriate control group
that would allow the panel to approve this device. One panel member suggested
that additional data supporting efficacy be presented, and that a human device
exemption (HDE) path might be discussed for extremely sick patients. Another
member suggested that a technical endpoint be used, and one suggested that the
follow-up data be longer than 6 months.

ADJOURNMENT

Dr. Laskey thanked
the participants and adjourned the meeting at 3:28 p.m.

I certify that I attended this
meeting of the Circulatory System Devices Advisory Panel Meeting on October 2,
2003, and that these minutes accurately reflect what transpired.